Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity.

Abstract

During the past decade a number of pesticides, industrial by-products, manufactured products such as plastics, and natural chemicals have been shown to disrupt the endocrine system. These chemicals are referred to as endocrine-disrupting chemicals (EDCs). These chemicals have received considerable attention, in part because endocrine disruption is a relatively unstudied area in toxicology and is only recently being taken into account in risk assessment. The focus here is on EDCs with estrogenic activity (EEDCs), which are chemicals that act as hormone mimics via estrogen receptor mechanisms; this is currently the largest group of known endocrine disruptors. The main purpose of this article is to present an overview of the mechanisms of hormone action that provide the basis for understanding how EEDCs have the potential to be biologically active at low, environmentally relevant doses. Our strategy is to discuss the receptor mechanisms mediating responses to a natural hormone, 17β-estradiol (E 2 ), and then to use this information as the basis for describing the low-dose effects of chemicals that disrupt the normal functioning of this hormonal system, either by mimicking, modulating, or antagonizing the activity of the hormone. We have chosen to use estrogen as our example because there is more known about the biology of estrogens and xenoestrogens than other components of the endocrine system for which there is evidence for disruption by environmental chemicals; however, the information presented here is applicable to endocrine disruptors that interfere with other hormonal systems.We will begin by briefly reviewing information concerning the relationship between dose, receptor occupancy, and responses (such as cell proliferation) after binding of E 2 to estrogen receptors (ER-α) in cultured human MCF-7 breast cancer cells. A number of specific factors influence the dose of an EEDC that reaches the target cells to produce a response. These factors include route of administration, absorption, distribution, metabolism, rate of clearance, plasma transport, cell uptake, affinity for estrogen receptor subtype in the cell, and the interaction of the ligand-receptor complex with tissue-specific factors comprising the transcriptional apparatus. This mechanistic information provides the basis for establishing the dose at the target site in cells (nuclear receptors associated with DNA or more recently identified receptors associated with the cell membrane) for an EEDC required to elicit a biological response similar to that produced by a dose of E 2 with equal estrogenic activity. Modeling that takes into account each of these factors would encompass physiologically based pharmacokinetic information (1), as well as quantitative structure-activity relationships (QSAR) (2,3). We have previously discussed the factors that influence access of E 2 and EEDCs from blood to estrogen receptors in cells elsewhere (4-6). Our primary focus in this review is on the latter part of the overall process that occurs once an estrogenic chemic...

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

“…1) The developmental (fetal) basis of adult disease: The developing fetus or infant is much more sensitive to endocrine-disrupting compounds than the adult; moreover, effects early in life may not be manifested until adulthood [63]. 2) Extremely low-dose exposures may exert significant effects on a developing organism, particularly if the exposure occurs during critical developmental periods [165,140,15,91]. Furthermore, effects are often manifested via non-traditional dose-response curves, similar to actions of steroid and nuclear receptor hormones [165,63].…”

“…2) Extremely low-dose exposures may exert significant effects on a developing organism, particularly if the exposure occurs during critical developmental periods [165,140,15,91]. Furthermore, effects are often manifested via non-traditional dose-response curves, similar to actions of steroid and nuclear receptor hormones [165,63]. 3) Environmental exposures generally occur in complex mixtures, as a contaminated environment is rarely affected by a single toxicant, and the effects may occur by more than one mechanism [15].…”

Low‐Dose Bisphenol A Exposure: A Seemingly Instigating Carcinogenic Effect on Breast Cancer

“…The U.S. EPA established a reference dose (RfD) for humans at 50 µg BPA/kg body weight (BW) day –1 based on a 1000‐fold reduction of the lowest observed adverse effect level (LOAEL) of 50 mg kg –1 BW day –1 15, 16. Some studies have indicated that the daily human intake of BPA is less than 1 µg kg –1 BW day –1 , rendering the RfD to be considered safe to humans 17.…”

Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A

“…However, the RfD for BPA (50 µg/kg/day) was calculated using the lowest observable adverse effect level (LOAEL) and 1,000-fold safety factors because a NOAEL had not been determined (Welshons et al 2003). More than 150 published studies describe BPA effects in animals exposed to < 50 mg/kg/day, including altered development of the male and female reproductive tracts, organization of sexually dimorphic circuits in the hypothalamus, onset of estrus cyclicity and earlier puberty, altered body weight, altered organization of the mammary gland, and cancers of the mammary gland and prostate; > 40 of these studies examined doses less than the RfD (Richter et al 2007).…”